SUMMARY The principal goal of this MIRA proposal from a distinguished PI with many years of uninterrupted NIH R01 funding and productive research in acute inflammation is to address the major gap and unmet need of understanding how humans survive sepsis, the highly lethal acute systemic inflammatory response driven by infection. Most sepsis deaths occur during organ and immune failure from dysregulated inflammation. No molecular-based specific therapies are available for this health dilemma. This proposal will develop a new and unifying theory of sepsis, according to which a persistent low-energy catabolic state, systemic inflammation inertia (SII), impedes oxidative metabolism and prevents failing immunity and organs from regaining the anabolic energy state needed to restore homeostasis. Mechanistically, this proposal's working model posits that a switch from a pro-oxidant anabolic state to a persistent antioxidant catabolic state underlies SII. It further theorizes that a functional cysteine thiol-based redox ?switchboard? located on key protein homeostats controls the equilibrium between anabolism and during sepsis, and that its rewiring causes bioenergetics failure and promotes high mortality sepsis. However, the theory predicts that SII is reversible and therapeutically targeting key homeostats can restore metabolic balance and enable immune system and organ recovery and improve sepsis survival. Consistent with the reversibility concept, independently targeted nuclear NAD+ dependent SIRT1 and mitochondrial PDK1 promote redox and bioenergy equilibrium and increase survival in a mouse model of sepsis-dependent SII, and proof of principle occurs in human sepsis blood monocytes. The PI's funded NIGMS and NIAID R01 grants consolidated in this MIRA provided early support for the energy ?supply-and-demand discrepancy? theory of how sepsis so often kills. Consolidating the PI's research program will maximize understanding and targeted treatment of a major public health dilemma, about which we are still insufficiently informed and which continues to be a major killer.